Citations

OBJECTIVE Electrical stimulation mapping is a widely used technique to determine functional localization for medically refractory epilepsy. Sites where stimulation interferes with naming are often focal regions of the frontal and temporal cortex. The extent to which these crucial sites remain in the same location over time in an individual adult patient has not yet been established. The aim of this study was to determine whether cortical naming sites identified using stimulation mapping are stable in their anatomical location over time in adult patients with medically refractory epilepsy. METHODS Twenty-two patients who underwent electrical stimulation mapping for medically refractory epilepsy during surgical interventions separated by more than 1 year between 1967 and 2005 were included. A median of 8.35 years elapsed between mappings. The mean age at the first operation was 27.7 (range 10–39) years. Fourteen patients were female. Mapping occurred under two different conditions: intraoperatively in procedures conducted under local anesthesia or extraoperatively through implanted grid electrodes. A Bayesian hierarchical model of language site locations across repeated interventions was used to assess the stability of locations of stimulation-evoked interference in language naming. RESULTS Sites where electrical stimulation interferes with language naming were separated by a median of 0.6 cm between the 2 mappings. Eighty-six percent of the mapped sites related to language naming at the second operation were within 1.5 cm of a site identified at the first operation, 61% within 1 cm, and 36% within 0.5 cm. However, in 2 patients, none of the identified language naming sites at the second operation were within 1.5 cm of the sites from the first operation. CONCLUSIONS This unique, long-term series of neurosurgical mappings reveals that language naming sites in the cortex of adult patients with epilepsy show substantial long-term stability over many years. However, rare relocation of these sites does occur in some patients over many years.

Abstract Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework’s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

Key Points In a cohort of children, 79% of families with kidney cysts had a monogenic diagnosis. Resolved cases were more likely to have a family history of kidney cysts and unresolved cases more often had unilateral cysts. Broad genetic testing revealed genetic diversity and informed prognosis and clinical management in childhood kidney cysts. Background Pediatric kidney cysts may indicate an underlying genetic disorder, yet the full spectrum of causes remains incompletely defined. With advances in genetic testing enabling broader evaluation, this study assessed the diagnostic utility of comprehensive genetic testing in a broad pediatric cohort with kidney cysts and characterized the underlying etiological diversity. Methods This observational cohort study included patients younger than 18 years enrolled between January 2020 and June 2024 at a single tertiary center. Genetic testing used targeted multigene or custom curated exome/genome sequencing panels, with segregation analysis when available. Eligible participants had at least two cysts without family history, one cyst with positive family history, or enlarged echogenic kidneys on prenatal ultrasound; those with congenital anomalies of the kidney and urinary tract associated with cysts were excluded. Clinical presentation was categorized as symptomatic, incidental, prenatal, or family screening. Primary outcomes were diagnostic yield and distribution of pathogenic variants. Results Among 109 patients (median age 7.6 years, 53% female), genetic testing identified a definitive diagnosis in 81 of 100 tested patients (81%) from 72 families (79%; 14 disorders). PKD1 variants were most common (45%), while PKD2 accounted for 7%. Other causes included HNF1B or 17q12 deletions (13%), minor autosomal dominant polycystic kidney disease genes (11%; GANAB, NEK8, IFT140 ), monoallelic PKHD1 (3%), and biallelic PKHD1 (8%), while syndromic ciliopathy genes accounted for 5%. A positive family history of cystic kidney disease was more common among patients with a genetic diagnosis (54% versus 11%; P = 0.008). Patients without an identified genetic diagnosis more often had unilateral cysts (26% versus 4%; P = 0.53). Diagnosis by clinical symptoms was the most genetically diverse category. Conclusions Comprehensive genetic testing in pediatric kidney cysts achieved high diagnostic yield in a selected cohort and identified diverse causes beyond major autosomal dominant polycystic kidney disease/autosomal recessive polycystic kidney disease genes, supporting early evaluation to improve diagnostic accuracy, inform prognosis, and guide management, even in the absence of family history.

Oversight of Artificial Intelligence in Human Subjects Research (AI HSR) presents unique challenges. These challenges arise from both the non-linear and iterative nature of AI development, as well as from the way AI shifts risk from individual research subjects to larger populations affected by AI-driven decisions and data handling. Traditional Institutional Review Boards (IRBs) often struggle to keep pace with these changes, which can lead to gaps in risk assessment and delays in the review process. There is a growing need for transparent, repeatable methods to manage AI risk in healthcare. This paper introduces the Three-Stage Framework, a risk-based oversight model designed to align ethical and regulatory review with an AI project’s stage of maturity and potential human impact. By aligning the level and timing of IRB review with the types of risks present at each stage of AI system development, the framework supports appropriate regulatory pathways and documents expectations while maintaining effective protection of human subjects. Through gradual, stage-appropriate documentation, the approach supports responsible and adaptive innovation while preparing AI systems for safe and ethical use across biomedical, social, behavioral, and educational domains. This approach prepares AI systems for safe and ethical use, accelerates compliant research, and helps IRBs and institutions maintain trustworthiness while protecting human subjects.

Abstract Multidrug efflux pumps transport antibiotics across the cellular membrane resulting in resistance conferred to the host organism. Efflux pump inhibitors (EPIs) potentiate the efficacy of antibiotics by blocking drug efflux and hold promise as adjuvant therapeutics in the fight against multidrug resistant pathogenic bacteria. A hurdle in the field has been the lack of selectivity of small molecule EPIs which often display off-target toxicity due to non-specific binding. To tackle this specificity challenge, we aimed to maximize an inhibitor’s binding surface area to efflux pumps by designing miniprotein EPIs using computational protein design and an E. coli co-expression assay to screen inhibition in cells. We used S. aureus NorA as a model efflux transporter since it confers drug resistance to fluoroquinolones, puromycin, and other cytotoxic compounds. Starting from a focused miniprotein library of only 86 members, we identified inhibitors in the screen that blocked NorA transport under active efflux conditions in vitro . Our most promising inhibitor I-23 was validated by solving a cryo-EM structure of the miniprotein in complex with NorA, which stabilized the transporter in the outward-open conformation. I-23 has a ferredoxin-like fold with one of its β-hairpins inserted into the substrate binding pocket of NorA and other parts of the globular fold occupying the shallow pocket and making extensive intermolecular contacts with NorA. An arginine residue on the tip of the hairpin loop was positioned near an anionic patch required for NorA antibiotic efflux. The identified structural motifs in this work could be employed to explore the molecular properties of peptidoglycan penetration; full realization of the therapeutic potential of the designed miniprotein inhibitors will require determining the principles for facilitating passage of ∼7 to 8 kDa miniproteins across the peptidoglycan bacterial cell wall.

Abstract The therapeutic landscape for systemic immunoglobulin light chain (AL) amyloidosis has been revolutionized by daratumumab-based regimens, achieving 76% 5-year overall survival in the landmark ANDROMEDA trial. However, the current prognostic models were developed using patient populations treated with now-suboptimal therapies, creating a critical gap between risk stratification models and contemporary outcomes. This comprehensive review analyzes prognostic factors and progression biomarkers in AL, categorizing them into disease-specific (clone-related and organ-related) and patient-specific factors. Notably, traditional baseline biomarkers including difference between involved and uninvolved free light chains and bone marrow plasma cell burden are losing prognostic significance with effective clone-directed therapies. Emerging approaches show promise, including dynamic markers such as minimal residual disease by free light chain mass spectrometry, cardiac imaging parameters such as global longitudinal strain, and functional measures. There is an urgent need for validation studies and prognostic model refinement to identify patients at high risk who may benefit from interventions beyond anti–plasma cell therapy.

Hazardous health behaviors increasingly contribute to end-stage liver diseases. To address surges in alcohol-associated liver disease and metabolic dysfunction–associated steatotic liver disease, clinicians in hepatology and liver transplantation must increasingly understand factors that influence eating and alcohol behaviors and consider ways to therapeutically influence patients’ health choices. Stigma is a prominent influence on patient behavior, but is overused as a sweeping explanatory factor as to why difficulties arise, behavior change does not occur, or when outcomes are suboptimal. With more awareness of behavioral influences, clinicians may wonder if, for all its adverse effects, stigma exerts some therapeutic effects on patients considering altering habits. While stigma is less likely to yield desired outcomes, other co-occurring systemic, social, and interpersonal influences can favorably affect health choices (ie, structural nudging, social norms and consequences, and motivational interviewing, respectively). In this article, we analyze these related yet distinct constructs in ways pertinent to liver disease and transplantation, indicating where they might be applied and further studied.

Abstract Background Ceftriaxone-resistant Escherichia coli infections are increasingly common, partially because of the emergence of E. coli sequence type 131 (ST131), including its subclade C2/H30Rx, which produce extended-spectrum β-lactamases. Methods A prospective cohort including 14 US sites, which enrolled monomicrobial ceftriaxone-resistant and susceptible E. coli bloodstream infection (BSI) cases in a 1:1 ratio, was used to compare ST131 versus non-ST131 E. coli BSI, with specific attention to E. coli ST131 C2/H30Rx. Desirability of outcome ranking was determined at 30 days after infection onset. Results This analysis included 282 patients with E. coli BSI; 43% (121/282) were E. coli ST131 and 23% (66/282) belonged to the C2/H30Rx subclade. Resistance to ceftriaxone was present in 79% (96/121) ST131, 86% (57/66) E. coli ST131 C2/H30Rx, and 27% (43/161) E. coli non-ST131. Compared to patients with non-ST131 E. coli BSI, patients with ST131 BSI were older (median 70 years, [Q1 62, Q3 76] years vs 65 years, [51, 74]; P = .005) and more often admitted from long-term care facilities (21/121 [17%] vs 7/161 [4%], P < .001). Overall and empiric carbapenem use was more frequent in the treatment of patients with ST131 BSI compared with non-ST131 BSI (overall 89/121 [74%] vs 50/161 [31%]; empiric: 58/121 [48%] vs 31/161 [19%], P < .001). Desirability of outcome ranking outcomes were similar between groups. Conclusions Most ceftriaxone-resistant E. coli from US patients with E. coli BSI belong to ST131, particularly E. coli ST131 C2/H30Rx, serving as an important driver of carbapenem use.

PURPOSE This national study was undertaken to determine screening mammography rates among transgender and gender diverse (TGD) individuals. METHODS TGD individuals and cisgender women who qualified to receive screening mammography based on American College of Radiology guidelines were identified in the longitudinal OptumLabs Data Warehouse. The primary end point was the percentage of patients who had high rates of screening (>75% recommended screenings). Multivariable analyses were conducted in a matched population of transgender men to cisgender women to identify and adjust for factors associated with high adherence. Individuals were matched at a 1:4 ratio (transgender men: cisgender women) on age, race/ethnicity, year of enrollment in their health care plan, and duration of follow-up. RESULTS This study focused on 10,478 TGD individuals (3,778 transgender men; 1,294 transgender women; 5,406 with gender dysphoria not meeting other TGD criteria, NMOT) and 6,218,369 cisgender women. For transgender men, transgender women, individuals with gender dysphoria NMOT, and cisgender women, high mammography rates were observed in 41.1% (95% CI, 39.5 to 42.6), 7.4% (95% CI, 6.0 to 8.8), 11.9% (95% CI, 11.0 to 12.7), and 38.3% (95% CI, 38.3 to 38.4), respectively ( P < .0001). When transgender men were compared with 15,112 matched cisgender women, an age-based differential association was observed between sex and high mammography rates (interaction P = .0003); compared with cisgender women, transgender men appeared more likely to manifest high rates of screening at age 40-49 years (odds ratios [ORs], 1.38 [95% CI, 1.28 to 1.50]; P < .0001) and 50-59 years (OR, 1.57 [95% CI, 1.35 to 1.81]; P < .0001) but not in the older age groups. CONCLUSION The relatively high rates of screening mammography in cisgender women and transgender men suggest clinicians are offering mammography to individuals who are at average or high breast cancer risk, as compared with cisgender women, and not to transgender women at low risk.

Abstract Cellular senescence has been implicated in the pathophysiology of radiotherapy-related bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of mouse femurs. In a proof-of-concept study, following two preclinical radiotherapy regimens of cumulative doses of 30Gy (5 x 6Gy) and 60Gy (5 x 12Gy), a senomorphic approach of JAKi treatment was more effective in alleviating radiation-related bone loss compared to the senolytic cocktail of D+Q. Early and intermittent suppression of SASP using JAK inhibitors alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression, reduced bone-marrow adiposity, and mitigated radiation related lymphatic impairment. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures. Lay Summary Radiotherapy as part of cancer treatment is correlated with an acute increase in senescent cells. Here we show that the pro-inflammatory senescence associated secretory phenotype (SASP) becomes much more prominent soon after radiotherapy in both patients and mice. Suppression of the SASP using a Janus kinase inhibitor, ruxolitinib, reduced the overall senescent cell burden, improved bone architecture by promoting bone formation, reduced bone marrow adiposity, and mitigated radiation-induced lymphatic impairment. Overall, these findings suggest that early inhibition of the SASP may help mitigate several bone anomalies and prevent long-term bone loss and fractures after radiotherapy. Graphical Abstract